The Resuscitation Outcomes Consortium (ROC), consisting of 9 Regional Clinical Centers and a Data and Coordinating Center, is conducting multiple collaborative trials to achieve its long-term objective of rapid translation of promising scientific and clinical advances to improve resuscitation outcomes in the out-of hospital setting. Having established unprecedented infrastructure to successfully accomplish this goal (using exception from informed consent under emergency circumstances) in 245 EMS agencies and nearly 35,000 EMS providers covering a population of over 22 million people throughout North America, ROC has already demonstrated its ability to rapidly advance the fields of emergency cardiac and trauma care. This proposal presents the rationale for a 6-year renewal of funding for ROC to continue to improve outcomes for these important national healthcare issues. Three of the specific aims of the Consortium are to further advance these fields by: 1) continuing to expand and investigate the cardiac arrest and traumatic injury Epistry database (already the largest available resource of its kind in the world), 2) complete ongoing cardiac arrest and traumatic injury studies in the next 18 months, and 3) implement and complete multiple additional cardiac arrest and traumatic injury clinical trials. The scientifically most premising trauma interventions, targeted for completion during the renewal period include, 1) immediate versus delayed intravenous fluid to decrease hemorrhage and subsequent reperfusion injury, 2) intravenous estrogen to decrease the magnitude of reperfusion injury, and 3) intravenous pentoxifylline to reduce release of inflammatory mediators and reactive oxidants after reperfusion. The scientifically most premising cardiac arrest interventions include: 1) continuous compressions versus standard CPR to improve survival, and 2) implementing therapeutic hypothermia immediately following restoration of circulation to reduce reperfusion injury and improve survival and qualitative outcome. The research design, rationale and techniques for achieving these proposals are specified in the application. Through this 6-year renewal, ROC will leverage its unparalleled infra-structure to significantly reduce morbidity and mortality from cardiac arrest and traumatic injury. Finally, the Toronto site also plans to expand training opportunities by applying for the Clinical Research Development Skills Core.